Follicle pool depletion: factors involved and implications.
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Adult↗
Biomedical subjects
B C Fauser
Publications and source records attributed to B C Fauser.
Gonadotropin-releasing hormone antagonist: new tools vs. old habits.
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Female↗
Implantation rates after in vitro fertilization and transfer of a maximum of two embryos that have undergone three to five days of culture.
OBJECTIVE: To evaluate implantation and pregnancy rates in patients undergoing IVF after the transfer of a maximum of two embryos that had been cultured for 3-5 days. DESIGN: Prospective study. SETTING: An IVF laboratory at a tertiary referral university hospital. PATIENT(S): One thousand seven hundred eighty-seven couples who underwent their first IVF cycle between January 1995 and December 1997. INTERVENTION(S): In vitro fertilization and transfer of embryos after 3, 4, or 5 days of culture using a single medium without coculture. MAIN OUTCOME MEASURE(S): Implantation and pregnancy rates. RESULT(S): Overall implantation and pregnancy rates were not significantly different with different culture periods. Forty-one percent of all available embryos developed into blastocysts on day 5. The transfer of at least one good-quality blastocyst could be performed in 62% of patients. Blastocysts had an implantation rate of 26% per embryo, whereas the implantation rate of eight-cell embryos on day 3 was 18%. Implantation rates for retarded, normal, and advanced embryos were not significantly different with an extended culture period. CONCLUSION(S): Under the study conditions, the transfer of embryos after 5 days rather than 3 days of embryo culture did not change the overall implantation and pregnancy rates. The implantation potential of embryos available for transfer can be assessed better after an extended culture period. Five days of culture allows the transfer of a reduced number of embryos without decreasing overall pregnancy rates.
Adult↗
Follicular and luteal phase characteristics following early cessation of gonadotrophin-releasing hormone agonist during ovarian stimulation for in-vitro fertilization.
Gonadotrophin-releasing hormone agonists (GnRHa) are widely used in in-vitro fertilization (IVF) for the prevention of a premature rise in luteinizing hormone (LH) concentrations. However, the administration of GnRHa during the follicular phase may also impair subsequent luteal function due to retarded recovery of pituitary gonadotrophin secretion. Therefore, luteal supplementation is generally applied. The present study was designed to determine whether a premature LH surge would still be prevented after early cessation of GnRHa during ovarian stimulation and whether subsequent luteal phase LH production would be sufficient to support progesterone synthesis by the corpus luteum. Sixty patients were randomized for three groups: (i) A long GnRHa/human menopausal gonadotrophin (HMG) protocol with luteal support by repeated human chorionic gonadotrophin (HCG) (n = 20), (ii) early follicular phase cessation of GnRHa without luteal support (n = 20), and (iii) a long GnRHa protocol without luteal support (n = 20). Frequent ultrasound and blood sampling was performed during the entire IVF cycle. Forty normo-ovulatory women served as controls. No premature LH surges were found after early cessation of GnRHa. In this group, some pituitary recovery occurred during the late luteal phase, but this did not affect corpus luteum function. Progesterone concentrations were shown to be dependent on disappearance of the pre-ovulatory bolus of HCG. Pregnancies occurred in all three groups. In conclusion, early follicular phase cessation of GnRHa is still effective in the prevention of a premature rise in LH. Although some pituitary recovery was observed thereafter, corpus luteum function is still abnormal due to early luteolysis.
Adult↗
Single monthly administration of the anti-progestagen Org 31710 in users of the 75 microg desogestrel progestagen-only pill: effects on pituitary-ovarian activity.
Endocrine and ultrasound effects were studied of an intermittent (every 28 days) oral administration of 150 mg of the anti-progestagen Org 31710 during the continued daily use of 75 microg desogestrel (DSG) for progestagen-only contraception. A randomized, double-blind, placebo-controlled two-centre study was conducted in 50 healthy volunteers. Serum luteinizing hormone (LH), follicle stimulating hormone (FSH), oestradiol and progesterone concentrations, and follicle number and size were studied, as well as endometrial thickness, which was assessed by transvaginal sonography at least twice weekly during a single medication cycle (cycle 3-5). Forty-eight women were evaluated (Org 31710, n = 25; placebo, n = 23). Seven ovulations were observed in the treated group versus none in the placebo group. LH concentrations were higher on days 9 and 11 and oestradiol concentrations lower on day 3 in the treated group, irrespective of whether ovulation occurred. No parameter could predict ovulation. Endometrial thickness was greater on cycle days 7-13 and 19 in the treated group. However, within the Org 31710 group, no significant differences were found in volunteers who did or did not ovulate. Observed differences may be attributed to a competitive effect of Org 31710 with progestagen-induced suppression of the pituitary-ovarian axis, altered oestradiol feedback mechanisms, and/or altered receptor availability.
Adolescent↗
Free androgen index and leptin are the most prominent endocrine predictors of ovarian response during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility.
We have previously demonstrated that obese hyperandrogenic amenorrheic women are less likely to ovulate after clomiphene citrate (CC) medication. The present study was designed to identify whether additional endocrine screening characteristics, all potentially involved in ovarian dysfunction in 182 normogonadotropic oligoamenorrheic infertile women, are associated with ovarian response, which may improve overall prediction of CC-resistant anovulation. Standardized endocrine screening took place before initiation of CC medication (50 mg/day; increasing doses up to 150 mg/day if required) from cycle days 3-7. Screening included serum assays for fasting insulin and glucose, insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), IGFBP-3, free IGF-I, inhibin B, leptin, and vascular endothelial growth factor. Forty-two women (22% of the total group) did not ovulate at the end of follow-up (a total number of 325 cycles were analyzed). Fasting serum insulin, insulin/glucose ratio, IGFBP-1, and leptin were all significantly different in univariate analyses (P < or = 0.02), comparing CC responders vs. nonresponders. Forward stepwise multivariate analyses in combination with factors reported earlier for prediction of patients remaining anovulatory after CC revealed a prediction model including 1) free androgen index (FAI = testosterone/sex hormone-binding globulin ratio), 2) cycle history (oligomenorrhea or amenorrhea), 3) leptin level, and 4) mean ovarian volume. These data suggest that decreased insulin sensitivity, hyperandrogenemia, and obesity, all associated with polycystic ovary syndrome, are prominent factors involved in ovarian dysfunction, preventing these ovaries from responding to stimulation by raised endogenous FSH levels due to CC medication. By using leptin instead of body mass index or waist to hip ratio, the previous model for prediction of patients remaining anovulatory after CC medication could be slightly improved (area under the curve from 0.82-0.85). This may indicate that leptin is more directly involved in ovarian dysfunction in these patients. The capability of insulin and IGFBP-1 to predict patients who remain anovulatory after CC disappears when FAI enters into the model due to a significant correlation between FAI and these endocrine parameters. This suggests that markers for insulin sensitivity (e.g. IGFBP-1 and insulin) are associated with abnormal ovarian function through its correlation with androgens, whereas leptin is directly involved in ovarian dysfunction.
Adult↗
Impact of ovarian hyperstimulation on the luteal phase.
The contemporary approach to ovarian stimulation in IVF treatment results in supraphysiological concentrations of progesterone and oestrogen in the luteal phase. These sex steroids act directly and indirectly to mature the endometrium, thus influencing its receptivity to implantation. The development of endometrial receptivity is a complex process that may be altered by inappropriate exposure to sex steroids. Alterations in the oestrogen to progesterone ratio, growth factor concentrations and cell adhesion molecule profiles may occur after ovarian stimulation, potentially affecting the receptivity of the endometrium. Recent clinical IVF studies have shown that implantation rates and corpus luteum function are influenced by oestrogen concentrations during the early luteal phase. Few comparative studies have been performed, but after ovarian stimulation there is a reduced implantation rate and a higher pregnancy loss rate before pregnancies can be detected clinically compared with natural cycle conceptions. Novel approaches to ovarian stimulation aimed at achieving a more physiological luteal phase endocrinology are now being developed. Data from a recent pilot study by our laboratory, involving minimal ovarian hyperstimulation and no luteal phase support, are discussed.
Animals↗
Increased loss of trabecular but not cortical bone density, 1 year after discontinuation of 2 years hormone replacement therapy with Tibolone.
OBJECTIVE: Assessment of loss of bone density (BD) 1 year after a 2-year period of hormone replacement therapy (HRT) with two doses of Tibolone as compared to placebo in early post-menopausal women. METHODS: Sixty-four out of 84 women (1-3 years following spontaneous menopause) who completed a 2-year randomised, placebo controlled study to evaluate effects of Tibolone participated in this follow-up study. Quantitative computed tomography was used to exclusively measure trabecular BD, microdensitometry of the mid-phalangeal shaft was used for estimation of cortical BD and biochemical markers of bone metabolism were assessed, 1 year after discontinuation of Tibolone. The study group received either placebo (n = 16), 1.25 mg/day Tibolone (n = 25) or 2.5 mg/day Tibolone (n = 23). RESULTS: Observations revealed a significantly greater decrease in trabecular BD during the post-trial year in both treatment groups compared to the placebo group (for 1.25 mg/day Tibolone, -6.0%, 95% CI -8.4 to -3.5; for 2.5 mg/day Tibolone, -10.0%, 95% CI: -12.9 to -6.9). In contrast, there was no significant difference in loss of phalangeal BD in both treatment groups compared to placebo. Biochemical markers (serum alkaline phosphatase, urinary excretion of hydroxyproline and calcium) do not suggest an increased bone turnover comparing Tibolone groups to placebo, 1 year after cessation of Tibolone. CONCLUSION: The present study suggests an increased loss of trabecular but not cortical BD as compared to the placebo group in the first year after cessation of HRT with Tibolone in early post-menopausal women.
Anabolic Agents↗
Activity of the pituitary-ovarian axis in the pill-free interval during use of low-dose combined oral contraceptives.
This study was performed to evaluate pituitary-ovarian recovery in the pill-free interval during use of three low-dose combined oral contraceptives (COC). Either the estrogen component or the progestin component was comparable in the study groups, to evaluate their relative influence. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) levels were measured and follicle number and size estimated by transvaginal sonography daily during the 7-day pill-free interval in 44 healthy volunteers using three different low-dose oral contraceptives. Healthy volunteers were enrolled using 20 micrograms ethinyl estradiol (EE) + 75 micrograms gestodene (GSD) (Harmonet, Wyeth-Lederle; n = 15), 20 micrograms EE + 150 micrograms desogestrel (DSG) (Mercilon, Organon n = 17), or 30 micrograms EE + 150 micrograms DSG (Marvelon, Organon, n = 12) given according to the usual regimen of one tablet daily during 3 weeks and 1 week pill-free interval. No ovulations were observed. Pituitary hormones were not statistically significantly different at the beginning of the pill-free interval between the study groups. FSH concentrations were significantly higher at the end of the pill-free interval in the 30 micrograms EE group compared with both 20 micrograms EE groups (7.0 [0.6-12.4] IU/L vs 4.9 [1.4-6.1] IU/L and 4.5 [2.4-7.4] IU/L; p = 0.001). In both 20 micrograms EE groups, a single persistent follicle (24 and 28 mm) was present in one subject. Follicle diameters were statistically significantly smaller at the beginning and at the end of the pill-free period in the 30 micrograms EE group compared with both 20 micrograms EE study groups. Dominant follicles (defined as follicle diameter > or = 10 mm) were observed at the end of the pill-free interval in both 20 micrograms EE groups (in 27% and 18% of women, respectively) but not in the 30 micrograms EE group. Finally, the area-under-the-curve for E2 was statistically significantly lower in the 30 micrograms EE group compared with both 20 micrograms EE groups. In conclusion, the EE content rather than the progestin component in the studied COC determined the extent of residual ovarian activity at the beginning of the pill-free interval. Dominant follicles were encountered only in the 20 micrograms EE study groups.
Adolescent↗
The brave new world of making babies.
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Female↗
Retrieval, maturation, and fertilization of immature oocytes obtained from unstimulated patients with polycystic ovary syndrome.
PURPOSE: Our purpose was to determine whether immature oocytes could be retrieved under local anesthesia, whether these oocytes would mature and fertilize in vitro, and whether adequate endometrium development could be obtained after hormonal supplementation. METHODS: Ovum pick-up was performed under local anesthesia. Immature oocytes were cultured and inseminated. To prepare the endometrium, estradiolvalerate was administered in combination with micronized progesterone. RESULTS: Immature oocytes were obtained in all cases. Fifty-six percent (n = 30) of the oocytes developed into metaphase II (MII) after 48 hr of culture, and another 20% reached the MII stage by 72 hr. Normal fertilization was observed in only 10% of oocytes inseminated. No embryonic development occurred, and therefore embryo transfer was not performed in any of the patients. Endometrial microbiopsy was performed in all subjects and endometrial development was considered sufficient in eight patients. CONCLUSIONS: We collected immature oocytes from patients with polycystic ovary syndrome without general anesthesia. In vitro maturation of these oocytes seemed adequate but fertilization rates were poor. Sufficient endometrial quality was obtained after hormonal substitution.
Adult↗
Diagnosis of subtle ovulation disorders in subfertile women with regular menstrual cycles: cost-effective clinical practice?
Serial monitoring by plasma progesterone measurement is advised in the literature for fertility work-up, to detect ovulation disturbances in women presenting with regular menstrual cycles. Three strategies to diagnose such 'subtle ovulation disorders' (SOD, defined as anovulation, inadequately timed ovulation or ovulation of a follicle of reduced size in regularly cycling women) were evaluated, in order to investigate costs of such a diagnosis. On the basis of a 'maximal', an 'ultrasound-only', and a 'preselection' strategy, total medical costs and costs including non-medical costs were calculated for each SOD diagnosis. A 'maximal' diagnostic strategy resulted in a total medical cost of ECU 9057 per diagnosis (including non-medical costs ECU 12,787); an 'ultrasound-only' strategy in ECU 4520 (ECU 6791) per diagnosis. By use of a 'preselection' strategy, 4.25% of the women were found to have an SOD, at a cost of ECU 3036 (ECU 6868) for each diagnosis. As the real significance of SOD diagnosis for the prognosis of the patient to become pregnant without treatment remains unclear, and as no randomized trials on treatment effectiveness have as yet been undertaken, it is questionable whether this approach is worthwhile.
Blood Chemical Analysis↗
Minimal ovarian stimulation for IVF: appraisal of potential benefits and drawbacks.
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Embryo Transfer↗
Aspects of ovarian follicle development throughout life.
The pool of primordial follicles present in the female ovary reaches its maximum number around 20 weeks of gestational age and then decreases in a logarithmic fashion throughout life until complete depletion occurs around the age of the menopause. Reproductive life is initiated when less than 10% (0.5 million) of primordial follicles are left. The entire growth trajectory of the follicle takes at least 3 months. Follicle growth up to the antral stage occurs during fetal life and infancy. While the role of gonadotropins in early follicular development remains controversial, the last 2 weeks of development are FSH dependent. The intercycle rise in FSH and decreasing levels thereafter are crucial for recruitment of a cohort of healthy, early antral follicles and subsequent single dominant selection. Following puberty, anovulation may persist for years and this may presage the development of adult anovulatory infertility. The menopause is preceded by a period of reduced fertility. The development of reliable and sensitive markers for ovarian ageing will be the challenge of the near future.
Adolescent↗
A new contributing factor to polycystic ovary syndrome: the genetic variant of luteinizing hormone.
Although the etiology of polycystic ovary syndrome (PCOS) is still unclear, LH is considered to play a central role in its pathogenesis. An immunologically anomalous form of LH, with two point mutations in the LHbeta gene, has been recently described. This genetic variant of LH (v-LH), of wide geographic distribution, is functionally different from wild-type (wt) LH. To assess the role of the v-LH in PCOS, we analyzed its frequency in groups of PCOS patients from Finland, The Netherlands, the United Kingdom, and the United States. The LH status was determined by two immunofluorometric assays from a total of 1466 subjects. The carrier frequency of the v-LH allele in the whole study population was 18.5%, being highest (28.9%) in Finland and lowest (11.2%) in The Netherlands. In the individual countries, the frequency of v-LH was similar in obese and nonobese controls, but in The Netherlands and Finland, it was 5- to 7-fold lower in obese PCOS subjects compared with that in the other groups (2-4.5% vs. 10.3-33.3%; P < 0.05). A similar tendency was found in the United States (5.7% vs. 11.1-25.0%), but not in the United Kingdom. The overall high prevalence of v-LH in healthy women and women with PCOS suggests that it is compatible with fertility. The similar frequency of v-LH in healthy nonobese and obese women indicates that obesity per se is not related to the variant. In contrast, the lower frequency of v-LH in obese PCOS patients suggests that v-LH somehow protects obese women from developing symptomatic PCOS. However, the regional differences in this finding between patients with apparently similar diagnostic criteria emphasizes the multifactorial nature of this syndrome, and that its pathogenesis may vary according to the genetic background. Although the definitive role of v-LH in PCOS remains to be proven, its determination may improve the prediction of risk of PCOS, especially in obese women.
Adolescent↗
Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility.
The present prospective follow-up study was designed to identify whether clinical, endocrine, or ultrasound characteristics assessed by standardized initial screening of normogonadotropic oligo/amenorrheic infertile patients could predict conception in 160 women who reached ovulation after clomiphene citrate (CC) medication. Additional inclusion criteria were total motile sperm count of the partner above 1 million and a negative history for any tubal disease. Daily CC doses of 50 mg (increasing up to 150 mg in case of absent ovarian response) from cycle days 3-7 were used. First conception (defined as a positive urinary pregnancy test) was the end point for this study. A cumulative conception rate of 73% was reached within 9 CC-induced ovulatory cycles. Patients who did conceive presented more frequently with lower age (P < 0.0001) and amenorrhea (P < 0.05) upon initial screening. In a univariate analysis, patients with elevated initial serum LH concentrations (>7.0 IU/L) had a higher probability of conceiving (P < 0.01). In a multivariate analysis, age and cycle history (oligomenorrhea vs. amenorrhea) were identified as the only significant parameters for prediction of conception. These observations suggest that there is more to be gained from CC ovulation induction in younger women presenting with profound oligomenorrhea or amenorrhea. Screening characteristics involved in the prediction of ovulation after CC medication in normogonadotropic oligo/amenorrheic patients (body weight and hyperandrogenemia, as shown previously) are distinctly different from predictors of conception in ovulatory CC patients (age and the severity of cycle abnormality). This disparity suggests that the FSH threshold (magnitude of FSH required for stimulation of ongoing follicle growth and ovulation) and oocyte quality (chances for conception in ovulatory cycles) may be differentially regulated.
Adult↗
Elevated serum levels of free insulin-like growth factor I in polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is the most common cause of anovulation in women. Previous studies suggest that the pathogenesis of PCOS may involve interrelated abnormalities of the insulin-like growth factor (IGF) and ovarian steroidogenesis systems. We investigated this hypothesis in fasting serum samples from 140 women with PCOS (age, 27.4 +/- 0.4 yr; body mass index, 26.3 +/- 0.5 kg/m2; mean +/- SEM). IGF-related parameters were also studied in a group of normoovulatory women (n = 26; age, 26 +/- 4 yr; body mass index, 23.6 +/- 4.3 kg/m2). For the PCOS group, the mean testosterone (T) level was 2.5 +/- 0.1 nmol/L, and it was significantly correlated with LH (r = 0.41; P < 10(-6)), estrone (r = 0.33; P = 0.016), estradiol (r = 0.18; P = 0.04), and androstenedione (AD; P < 10(-6)), but not with dehydroepiandrosterone sulfate (P = 0.71), a marker of adrenal steroidogenesis. T and AD were also related to total ovarian follicle number and ovarian size, as previously found with normoovulatory women (1). There were no differences between the PCOS subjects and the normoovulatory group for total IGF-I, IGF-II, or IGF-binding protein-3 (IGFBP-3). However, IGFBP-1 levels were significantly decreased in the PCOS group (1.0 +/- 0.2 vs. 7.3 +/- 1.1 ng/mL; P < 0.001) and were inversely correlated with serum insulin levels (r = -0.50; P < 10(-8)). Serum levels of free IGF-I (fIGF-I) were elevated (5.9 +/- 0.3 vs. 2.7 +/- 0.3 ng/mL; P < 0.001) in inverse relation with IGFBP-1 (r = -0.31; P = 0.046). Serum fIGF-I levels were related to total follicle number (r = - 0.35; P < 10(-4)) and to the ratio of sex hormone-binding globulin to T (r = -0.23; P = 0.009). However, these relationships were not independent of other variables. Despite the more than 2-fold elevation in fIGF-I levels, significant relationships between fIGF-I and markers of ovarian steroidogenesis (T, AD, estradiol, and estrone) could not be demonstrated. In conclusion, although we confirmed correlations between LH and hyperandrogenemia and have found abnormalities in the IGF system in a large cohort of PCOS subjects, a direct relationship between hyperandrogenism and the IGF system could not be shown. Previous studies suggest that elevated LH and hyperinsulinemia lead to excess ovarian androgen synthesis in PCOS and that the intraovarian IGF system is important for normal follicle development and may be important in the arrested state of follicle development in PCOS. However, the data presented in this cross-sectional study suggest that insulin-related changes in circulating IGFBP-1 and subsequent elevation of fIGF-I reflect insulin resistance and have little enhancing effects on ovarian steroidogenesis in this disorder.
Adult↗
Hormone patterns after induction of ovulation with clomiphene citrate: an age-related phenomenon.
Since the introduction of clomiphene citrate (CC), more than three decades ago, a discrepancy has been observed between ovulation and pregnancy rates for which as yet no explanation exists. To investigate if ovulation disorders or abnormal hormonal patterns occur more often in CC-stimulated seemingly ovulatory cycles, we performed hormonal and sonographic monitoring in first cycles of oligo- or amenorrheic patients who were stimulated with 50 mg CC, and compared the hormonal patterns to those in natural cycles of age-matched proven fertile women. Twenty-four first CC cycles were monitored. Twelve cycles appeared to be ovulatory, eleven showed no follicle development and one cycle exhibited the luteinized unruptured follicle (LUF) phenomenon. Ten ovulatory cycles were compared with 27 unstimulated control cycles. In four cycles stimulated by CC, a temporary decline in estradiol levels was apparent. In these cycles, estradiol reached a higher level on cycle day (CD) 7 or 8 compared to cycles without a decline. Such an estradiol decline was seen in only one control cycle. Furthermore, the estradiol levels on CD 7 or 8 appeared to be age-related. We conclude that the estradiol decline in CC-stimulated ovulatory cycles may be a consequence of a sharp rise after CC stimulation, and such a rise may be age-related and coincide with a diminished follicle quality. If this phenomenon is associated with a suboptimal cycle, and so contributes to the suboptimal pregnancy rates after ovulation-induction treatment with clomiphene citrate, is still unknown.
Adult↗